PROJECT SUMMARY/ABSTRACT In this K23 career development award, Dr. Kaitlin Casaletto will develop training in biologically-targeted lifestyle strategies for the prevention of age-related cognitive decline. Dr. Casaletto is a postdoctoral fellow in clinical neuropsychology who will be transitioning to faculty at the University of California, San Francisco Memory and Aging Center (MAC). Her longer term goal is to become a leading clinical aging researcher developing behaviorally-based interventions to promote brain health and improve patient outcomes with age. Through the support of this K23 and the enriched transdisciplinary training environment and resources at the MAC, Dr. Casaletto aims to accomplish the following training goals: 1) gain expertise in the neurobiology of aging with a focus on environmentally modifiable pathways; 2) develop specialized proficiency in plasma and cerebrospinal fluid (CSF) biomarker analytic platforms for clinical research; 3) expand skills in randomized trial design; 4) translate the K23 training and findings into an R01 developing a behavioral intervention to prevent age-related neurodegeneration. To achieve these goals, Dr. Casaletto has assembled an exemplary mentorship team, including her primary mentor, Dr. Joel Kramer, a neuropsychologist with decades of research dedicated to the measurement of behavior and cognition in aging; co-mentor, Dr. Kristine Yaffe, a professor of neurology, psychiatry, and epidemiology who is a leader in the identification of lifestyle prevention factors in AD; collaborator, Dr. Lennart Mucke, a neurobiologist who investigates and directs a UCSF-affiliated institute characterizing the mechanisms of neurodegenerative diseases; collaborator, Dr. Henrik Zetterberg, a neurochemist who developed the CSF biomarkers proposed in this K23; collaborator, Dr. Adam Gazzaley, a neuroscientist who directs a research center developing technologies to optimize brain function; and collaborator, Dr. John Neuhaus, a biostatistician with expertise in advanced modeling of biomedical data. The overarching goal of the proposed study is to characterize the relationship between lifestyle cognitive and physical behaviors and proteomic markers of neural health in aging and AD. The central rationale is that neural plasticity occurs throughout adulthood, is dysregulated in AD, and can be induced with behaviors. Though modifiable lifestyle factors are estimated to account for >9 million AD cases worldwide, behavioral prevention strategies have not been neurobiologically-targeted, limiting their potency. First, we will determine the relationship between daily cognitive and physical behaviors and protein markers of neural function in plasma and CSF in adults at-risk for and with AD. These models will be replicated in an independent sample. Second, we will manipulate cognitive and physical behaviors using a randomized training experiment and determine the directional impact on neural protein concentrations. This translational project will identify daily activities that can be used to improve neural health in aging and, ultimately, be leveraged to develop behavior-based interventions to prevent AD.